Antiischemic effect of monophosphoryl lipid A in conscious rabbits with hypercholesterolemia and atherosclerosis.

We studied whether monophosphoryl lipid A (MLA), an endotoxin derivative, protected the heart from planned ischemia in hypercholesterolemic conscious rabbits. Normal and hypercholesterolemic (8-week exposure to 1.5% cholesterol-enriched diet) conscious rabbits with right ventricular electrode and left ventricular polyethylene catheters were subjected to ventricular overdrive pacing (VOP: 500 beats/min over 10 min = control VOP). The resulting intracavitary ST-segment elevation, increase in left ventricular end-diastolic pressure (LVEDP), and a reduction of ventricular effective refractory period (VERP) were measured. Three days later the animals were given a single intravenous bolus of 10 or 30 microg/kg MLA or its solvent or both, and a second VOP (test VOP) was applied 24 h later. MLA decreased ST elevation and LVEDP increase from 2.1 +/- 0.16 to 1.27 +/- 0.25 and 0.97 +/- 0.13 mV and 14.6 +/- 1.2 to 11.1 +/- 1.0 and 12.4 +/- 1.2 mm Hg in normal animals and from 2.55 +/- 0.14 to 1.31 +/- 0.12 and 0.96 +/- 0.30 mV and from 21.0 +/- 1.6 to 11.7 +/- 1.3 and 12.4 +/- 1.3 mm Hg in atherosclerotic animals after 10- and 30-microg/kg doses, respectively (p < 0.001 for each). VOP-induced VERP reduction was also significantly alleviated by both MLA doses; nevertheless, 30-microg/kg MLA significantly prolonged resting VERP with a slight VERP reduction in response to pacing in both normal and atherosclerotic animals. We conclude that MLA produces a delayed antiischemic effect in both normal and hypercholesterolemic/atherosclerotic conscious rabbits.